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Antiangiogenic Agents in Cancer Therapy

Antiangiogenic Agents in Cancer Therapy

ABSTRACT: There is substantial preclinical and clinical evidence that angiogenesis plays a role in the development of tumors and the progression of malignancies. Inhibiting angiogenesis has been shown to suppress tumor growth and metastasis in many preclinical models. These benefits have translated to the clinic with both marketed and investigational antiangiogenesis agents. The most prominent target of these compounds is vascular endothelial growth factor (VEGF) and its receptors. However, several other factors are of interest as well. These include integrins, matrix metalloproteinases, and endogenous antiangiogenic factors. Data from late-stage clinical trials support the role of antiangiogenic agents in cancer therapy and the significant role that VEGF plays in angiogenesis. Future research will focus on determining the tumor types and stages that will benefit most from antiangiogenic therapy and combining therapies that target different factors in the angiogenesis pathway.

There is substantial preclinical
and clinical evidence that angiogenesis
plays a role in the
development of tumors and the progression
of malignancies. As reviewed
by Rakesh Jain in this supplement
(see page 7), new tumors cease to
grow beyond 1 to 3 cm without an
additional blood supply. Once the angiogenic
switch has occurred, the formation
of new vessels begins, feeding
the developing tumor and making it
possible for it to progress. The number
of new vessels formed, termed
microvessel density, correlates with
prognosis in many tumor types.

This increased blood supply might
be expected to aid in the delivery of
chemotherapy to the tumor, but such is
not the case. The tumor vasculature is
irregularly shaped, disorganized, and
highly permeable. This permeability
contributes to high interstitial fluid pressure
within the tumor, which inhibits
the effective delivery of chemotherapy
to the tumor tissue. The inefficient blood
flow associated with this dysfunctional
vasculature further impedes the delivery
of chemotherapy. In addition, this
dysfunctional vasculature can hinder
tumor oxygenation, thereby promoting
resistance to radiation.

These effects of angiogenesis make
this abnormal process in tumor development
an attractive target for therapeutic
intervention. A large number
of endogenous pro- and antiangiogenic
factors tightly regulate the process.
Of these, the most prominent and well
researched is vascular endothelial
growth factor (VEGF). A phase III
trial of the currently marketed monoclonal
antibody to VEGF-A (referred
to as VEGF), bevacizumab (Avastin),
added to conventional cytotoxic chemotherapy
showed greater survival in
patients with metastatic colorectal cancer.[
1] Many other agents that target
VEGF and other factors in the regulation
of angiogenesis are being developed.
This article reviews agents currently
marketed or in clinical development
that target these factors.

Current Antiangiogenic
Therapies

A large number of agents that target
angiogenesis are in clinical development.
They can be broadly
classified as agents that have been
developed primarily for their antiangiogenic
activity (Table 1), and those
that have been developed or used for
other biologic effects but also have
antiangiogenic activity (Table 2).[2]
This review focuses on those that have
been developed primarily as antiangiogenic
agents.

VEGF-Targeted Agents
By far the greatest number of antiangiogenic
drugs currently in clinical
development target the VEGF pathway.
As reviewed by Jain in this supplement,
VEGF is crucial in the angiogenic
process, making this pathway a
logical target. VEGF belongs to a family
of seven factors (Table 3). VEGF
and its isoforms are the ligands for
VEGF receptors (VEGFR)-1 and -2.
Although VEGF binds to two receptor
tyrosine kinases, VEGFR-1 (also
known as Flt-1) and VEGFR-2 (also
known as KDR), the angiogenic effects
are primarily exerted through
binding to VEGFR-2.[3] The binding
of VEGF to these receptors on
endothelial cells results in receptor
dimerization and activation, which
stimulates signaling cascades involving
phospholipase C, protein kinase
C, the Src tyrosine kinases, MAP kinase,
phosphatidylinositol-3-kinase
(PI3K), Ras GTPase-activating protein,
and the Raf-Mek-Erk pathway
(reviewed in [4,5]) (Figure 1). Additionally,
VEGF binds to the non-
tyrosine kinase neuropilin receptors
(NRP-1 and NRP-2). NRP-1 can act as
a coreceptor for VEGF, and as such
potentiates VEGFR-2-dependent endothelial
cell mitogenesis.

Recently it has also been determined
that NRP-1 regulates endothelial
cell adhesion to extracellular
matrix proteins, independent of
VEGFR-2.[6] NRP-1 is also expressed
on tumor cells and often is the sole
VEGF receptor on these cells. Binding
of VEGF to NRP-1 on tumor cells
promotes tumor cell survival,[7] proliferation,[
8] and chemotaxis.[9] The
function of NRP-2 is as yet unclear
but it is likely involved in lymphangiogenesis.

Agents targeted toward VEGF act
by antagonizing VEGF itself, blocking
its receptors, inhibiting its synthesis,
or inhibiting proteins in the VEGF
receptor-signaling cascade. Most of
these actions are targeted toward vascular
endothelial cells; however, direct
effects on tumor cells are possible
through inhibiting interaction of VEGF
with NRP-1 and with VEGFR-2 in the
isolated cases in which this receptor is
expressed on tumor cells (Figure 2). As
reviewed by Jain in this supplement,
there are two key mechanisms by which
the antagonism of VEGF suppresses
tumor growth and inhibits metastasis:
prevention of neovascularization[10,11]
and improvement of chemotherapy delivery.[
12]

  • Anti-VEGF Agents-
    Several
    agents specifically antagonize VEGF,
    the most notable of which is bevacizumab,
    a humanized monoclonal antibody
    to all isoforms of VEGF.
    Bevacizumab has been approved for
    use in combination with fluorouracil
    (5-FU)-based chemotherapy as firstline
    treatment of metastatic colorectal
    cancer.[13] The pivotal phase III clinical
    trial of bevacizumab in combination
    with irinotecan (Camptosar),
    5-FU, and leucovorin in metastatic
    colorectal cancer showed greater median
    survival with the combination
    than with chemotherapy alone (20.3
    vs 15.6 months; P < .001).[1] This
    finding with an agent whose primary
    mechanism of action is antiangiogenesis
    has sustained optimism for this
    mode of anticancer therapy. Furthermore,
    this benefit occurred in the absence
    of few significant additional side
    effects relative to chemotherapy. Grade
    3 hypertension was more common in
    bevacizumab-treated patients (11% vs
    2.3%), but was manageable.[1]
  • Randomized studies with bevacizumab
    have shown clinical efficacy in
    other cancers as well. Response rates
    were higher and times to progression
    were longer with bevacizumab added
    to carboplatin (Paraplatin) and paclitaxel
    than with chemotherapy alone
    in patients with advanced or recurrent
    non-small-cell lung cancer
    (NSCLC).[14] The overall response
    rates in metastatic breast cancer were
    higher with bevacizumab added to
    capecitabine than with capecitabine
    alone.[15]

    In neither of these trials was survival
    greater with the addition of bevacizumab,
    however, suggesting that
    earlier treatment with an anti-VEGF
    agent in these settings may be required.
    A number of recent clinical
    trials (eg, BOND-2) are testing combinations
    of bevacizumab and agents
    that antagonize the epidermal growth
    factor receptor (EGFR)[16-20]; their
    results are eagerly awaited.

    Other anti-VEGF agents include
    VEGF-trap, a recombinant protein that
    consists of the extracellular domains
    of human VEGFR-1 and human
    VEGFR-2 fused to human IgG1 Fc,
    and antisense oligonucleotide
    VEGF (VEGF-AS, Veglin).[21,22]
    VEGF-trap inactivates all isoforms
    of VEGF(-A),[21] and VEGF-AS
    inhibits receptor binding and expression
    of VEGF-A, -C, and -D.[22] Both
    have been well tolerated in phase I
    trials. Dose-related hypertension
    occurred with VEGF-trap, but no
    dose-limiting toxicities were apparent
    with VEGF-AS. Both have shown
    early evidence of antitumor efficacy.[
    21,22]

  • Anti-VEGF Receptor Agents-
    Of the agents that target VEGF receptors,
    the most numerous and the
    furthest along in clinical trials are the
    VEGF receptor tyrosine kinase inhibitors.
    These block or compete with
    the binding of ATP, inhibiting receptor
    phosphorylation and the subsequent
    intracellular signaling cascade.
    Phase III trials of two of these agents
    are planned or are under way: vatalanib
    (PTK787), which has activity
    against VEGFR-1, -2, and -3, and
    SU011248, which has activity against
    VEGFR-2 and platelet-derived growth
    factor receptor (PDGFR).
  • Phase I/II trials of vatalanib in combination
    with 5-FU-based chemotherapy
    for metastatic colorectal cancer
    showed good tolerability at doses up
    to 1,250 mg/d. Grades 3 and 4 adverse
    events included hypertension,
    fatigue, ataxia, neutropenia, thrombocytopenia,
    and dizziness.[23,24] The
    partial response rates ranged from
    33% to 50%, and phase III trials in
    this setting are ongoing.[24] The adverse
    events in phase I/II trials of
    SU011248 included fatigue and asthenia,
    nausea and vomiting, diarrhea,
    neutropenia, thrombocytopenia, lymphopenia,
    and decreased left ventricular
    ejection fraction of > 20%.[25,26]
    The dose-limiting toxicity with doses
    greater than the recommended
    50 mg/d was fatigue and asthenia.[25]
    Antitumor efficacy was shown in a
    phase II trial of SU011248 in patients
    with previously treated metastatic renal
    cell carcinoma.[26] There were
    partial responses in 24% of patients
    and stable disease in 46%. A phase III
    trial is planned.

    Despite the promising results with
    these agents, some in this class have
    failed in clinical trials due to poor
    efficacy and safety. Semaxinib
    (SU5416), which was active against
    VEGFR-1, -2, PDGFR, Flt-4, and
    c-kit, was associated with a high incidence
    of thrombotic events[27] and
    showed no increase in 1-year eventfree
    survival in a phase II trial in patients
    with renal cell carcinoma.[28]
    Similarly, no recent data have been
    reported on a related molecule,
    SU6668, which is active against
    VEGF, PDGF, and fibroblast growth
    factor-1 receptors. The reason for the
    delay or discontinuation of the development
    of SU6668 is not clear, but
    phase I trials showed self-inducing
    clearance, which resulted in difficulty
    in maintaining pharmacologically
    active concentrations with the maximum
    tolerated dose.[29-31]

    Other VEGF receptor-targeted
    agents include a raf kinase inhibitor,
    sorafenib (BAY 43-9006), and a
    chimeric monoclonal antibody to
    VEGFR-2, IMC-1C11, with sorafenib
    being the furthest along in development.
    In a phase II trial there was a
    response to sorafenib in 25 (40%) of
    63 assessable patients with metastatic
    renal cell carcinoma.[32] The most
    common grade 3 adverse events were
    hand-foot skin reaction, rash, fatigue,
    and hypertension.[32]

    Good tolerability was shown with
    IMC-1C11 in phase I trials, but human
    antichimeric antibodies developed
    in half of the patients, and a
    second-generation human monoclonal
    antibody is being developed.[33]

  • Other VEGF-Targeted Agents-
    Other agents that act on the VEGF
    pathway include AE-941 (Neovastat)
    and enzastaurin (LY317615). AE-941
    is a derivative of shark cartilage that
    prevents VEGF from binding to its
    receptors and also inhibits matrix metalloproteinase
    (MMP) activity.
    AE-941 did not meet its primary end
    point, longer median overall survival,
    in a phase III trial in patients with
    renal cell carcinoma, but significantly
    longer survival was seen in the
    subgroup of healthier patients with
    clear cell histology and only one
    metastatic site (26.3 months with
    AE-941 vs 12.6 months with placebo;
    P = .02).[34] The agent is also very
    well tolerated.[35,36] Its development
    continues, and a phase III trial in
    NSCLC is ongoing.
  • Enzastaurin is an inhibitor of the
    protein kinase C-β isozyme, which is
    activated by VEGF and potentiates
    the effects of VEGF.[37] It is currently
    in phase I trials.[38]

    Agents That Do Not Target
    the VEGF Pathway

    Several investigational antiangiogenic
    drugs are aimed at targets other
    than the VEGF pathway, including
    endogenous antiangiogenic factors,
    integrin inhibitors, enzyme inhibitors,
    and vascular-disruptive agents. None
    of these, however, have yet advanced
    to phase III clinical trials. Those in
    phase II trials are discussed here.

  • Antiangiogenic Factors-
    Proteins
    that mimic naturally occurring
    antiangiogenic factors have been developed.
    Those on which phase II data
    are available include recombinant human
    angiostatin and endostatin. Preliminary
    phase II data on angiostatin
    in combination with paclitaxel and
    carboplatin in patients with NSCLC
    show partial responses in 39% and
    stable disease in 39% of 23 patients.[
    39] The duration of response
    was 8 months or longer in four of
    these patients. The most common adverse
    event was rash, in 92% of patients
    (grade 1 in 75%). There were
    few adverse events in phase I trials of
    angiostatin monotherapy, mainly
    grade 1 or 2 injection-site reactions.[
    40,41] Hemorrhage in central
    nervous system metastases occurred
    in two patients, and deep-vein thrombosis
    in two.[41] Long-term treatment
    (>1 year in five patients) resulted in
    no additional treatment-related adverse
    events.[41] A phase II study of
    endostatin in patients with advanced
    neuroendocrine tumors showed stable
    disease in 62% of patients.[42]
    The only severe adverse event was
    myocardial infarction in a patient with
    prior coronary artery disease.
  • Integrin-Targeted Agents-
    Several
    molecules have been designed to
    target αv integrins. Integrins are heterodimeric
    cell-surface receptors that
    play an important role in endothelial
    cell migration, proliferation, and survival.[
    43] Two molecules are in phase
    II trials: MEDI-522 (Vitaxin) and
    cilengitide (EMD 121974). MEDI-
    522 is a humanized monoclonal antibody
    to αvβ3.[44] Phase I trials showed
    an absence of serious adverse events
    other than infusion-related reactions.[
    44,45] Cilengitide is a peptide
    that contains the Arg-Gly-Asp (RGD)
    sequence. This sequence is present on
    integrins and is a binding epitope that
    is shared by many integrin ligands.
    Thus, RGD-containing peptides are
    thought to antagonize integrin-mediated
    actions.[43] Phase I trials showed
    no dose-limiting toxicities.[43,46]
    Phase II trials of both MEDI-522 and
    cilengitide are ongoing.
  • Other Agents-
    A number of
    agents aimed at other targets have also
    been developed. These include the
    MMP inhibitor BMS-275291, the
    heparanase inhibitor PI-88, and a
    group of agents referred to as vascular-
    disruptive agents that attack existing
    tumor vasculature rather than
    prevent the formation of new vessels.
    BMS-275291 is a nonhydroxamate
    MMP inhibitor that has been designed
    to inhibit only MMPs that are not
    sheddases. It is thought that the inhibition
    of sheddases contributes to the
    arthrotoxicity associated with older
    hydroxamate MMP inhibitors.[47]
    Grade 2 or higher musculoskeletal
    symptoms developed in approximately
    a third of the patients in two phase
    II trials.[48,49] The drug was administered
    in both trials with paclitaxel,
    which is well known for causing
    arthralgias; however, the trials were
    randomized and the trial in breast cancer
    was halted early because of greater
    toxicity in the BMS-275291 group.[49]
    The trial in NSCLC, on the other hand,
    found no difference in arthrotoxicity
    between those receiving BMS-275291
    and those receiving placebo (both
    along with paclitaxel and carboplatin),
    and patient accrual to a phase III trial
    is ongoing.[48]

    PI-88 inhibits heparanase, an enzyme
    that causes the release of proangiogenic
    factors from the extracellular
    matrix.[50] Good tolerability and evidence
    of efficacy with PI-88 in phase
    I trials has led to continued
    study.[50,51] A phase II trial in multiple
    myeloma showed disease stabilization
    in 39% of patients.[51] Phase
    II trials in melanoma, liver cancer,
    and NSCLC are ongoing.[51]

    Four small-molecule vascular-disruptive
    agents are in clinical trials.[52]
    Three of these, combretastatin A4,
    ZD6126, and AVE8062, cause the destruction
    of tumor vasculature through
    tubulin depolymerization of proliferating
    endothelial cells. The fourth,
    5,6-dimethylxanthenone-4-acetic
    acid, is a flavonoid that induces the
    release of tumor necrosis factor from
    intratumoral macrophages. Combretastatin
    A4 is the furthest along in
    development, with phase II trials ongoing.
    The most common dose-limiting
    adverse event in phase I trials was
    tumor pain.[53,54] Others were acute
    coronary syndrome, ataxia, and motor
    neuropathy.

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